The plant triterpenoid celastrol blocks PINK1-dependent mitophagy by disrupting PINK1's association with the mitochondrial protein TOM20

Zhang, Conggang; Wang, Rongchun; Liu, Zeyu; Bunker, Eric; Lee, Schuyler; Giuntini, Michelle; Chapnick, Douglas A.; Liu, Xuedong

doi:10.1074/jbc.ra118.006506

Cited by 23 publications

(11 citation statements)

References 55 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Medicine have become important choices for the treatment of several chronic diseases, including liver fibrosis. 5,7 Celastrol is a pentacyclic triterpenoid compound 8,9 (the chemical structure of celastrol is shown in Figure 1), which is isolated from a common clinical used Traditional Chinese Medicine named Tripterygium wilfordii Hook F.…”

Section: The Active Ingredients Extracted From Traditional Chinesementioning

confidence: 99%

“…The active ingredients extracted from Traditional Chinese Medicine have become important choices for the treatment of several chronic diseases, including liver fibrosis . Celastrol is a pentacyclic triterpenoid compound (the chemical structure of celastrol is shown in Figure ), which is isolated from a common clinical used Traditional Chinese Medicine named Tripterygium wilfordii Hook F. Celastrol possesses multiple pharmacological effects and showed potent anti‐inflammatory effect against many disease models, and however, few reports can be seen regarding the anti‐inflammatory potential of celastrol in liver fibrosis. SIR2 is a family of histone deacetylases and is widely distributed in cells with multiple functions .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Celastrol exerts anti‐inflammatory effect in liver fibrosis via activation of AMPK‐SIRT3 signalling

Wang

et al. 2019

J Cellular Molecular Medi

View full text Add to dashboard Cite

Celastrol, a pentacyclic tritepene extracted from Tripterygium Wilfordi plant, showing potent liver protection effects on several liver‐related diseases. However, the anti‐inflammatory potential of celastrol in liver fibrosis and the detailed mechanisms remain uncovered. This study was to investigate the anti‐inflammatory effect of celastrol in liver fibrosis and to further reveal mechanisms of celastrol‐induced anti‐inflammatory effects with a focus on AMPK‐SIRT3 signalling. Celastrol showed potent ameliorative effects on liver fibrosis both in activated hepatic stellate cells (HSCs) and in fibrotic liver. Celastrol remarkably suppressed inflammation in vivo and inhibited the secretion of inflammatory factors in vitro. Interestingly, celastrol increased SIRT3 promoter activity and SIRT3 expression both in fibrotic liver and in activated HSCs. Furthermore, SIRT3 silencing evidently ameliorated the anti‐inflammatory potential of celastrol. Besides, we found that celastrol could increase the AMPK phosphorylation. Further investigation showed that SIRT3 siRNA decreased SIRT3 expression but had no obvious effect on phosphorylation of AMPK. In addition, inhibition of AMPK by employing compound C (an AMPK inhibitor) or AMPK1α siRNA significantly suppressed SIRT3 expression, suggesting that AMPK was an up‐stream protein of SIRT3 in liver fibrosis. We further found that depletion of AMPK significantly attenuated the inhibitory effect of celastrol on inflammation. Collectively, celastrol attenuated liver fibrosis mainly through inhibition of inflammation by activating AMPK‐SIRT3 signalling, which makes celastrol be a potential candidate compound in treating or protecting against liver fibrosis.

show abstract

Section: The Active Ingredients Extracted From Traditional Chinesementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Celastrol exerts anti‐inflammatory effect in liver fibrosis via activation of AMPK‐SIRT3 signalling

Wang

et al. 2019

J Cellular Molecular Medi

View full text Add to dashboard Cite

show abstract

“…In addition, both receptors of the TOM complex, TOM20 and TOM70, were suggested by two different studies to play an important role in PINK1 recognition at the MOM. Zhang et al [ 15 ] reported a drastic effect of TOM20 inhibition by celastrol on PINK1 association with mitochondria, and Kato et al [ 16 ] showed that PINK1 relies on the TOM70 receptor for its import into healthy mitochondria. Collectively, it seems that various subunits of the TOM complex contribute by an undefined way to the association of PINK1 with the MOM.…”

Section: Introductionmentioning

confidence: 99%

The role of the individual TOM subunits in the association of PINK1 with depolarized mitochondria

et al. 2022

View full text Add to dashboard Cite

Mitochondria dysfunction is involved in the pathomechanism of many illnesses including Parkinson’s disease. PINK1, which is mutated in some cases of familial Parkinsonism, is a key component in the degradation of damaged mitochondria by mitophagy. The accumulation of PINK1 on the mitochondrial outer membrane (MOM) of compromised organelles is crucial for the induction of mitophagy, but the molecular mechanism of this process is still unresolved. Here, we investigate the association of PINK1 with the TOM complex. We demonstrate that PINK1 heavily relies on the import receptor TOM70 for its association with mitochondria and directly interacts with this receptor. The structural protein TOM7 appears to play only a moderate role in PINK1 association with the TOM complex, probably due to its role in stabilizing this complex. PINK1 requires the TOM40 pore lumen for its stable interaction with the TOM complex and apparently remains there during its further association with the MOM. Overall, this study provides new insights on the role of the individual TOM subunits in the association of PINK1 with the MOM of depolarized mitochondria. Key messages TOM70 is the main receptor for the import of PINK1 into mitochondria. TOM20 plays only a minor role in PINK1 recognition at the organellar outer membrane. PINK1 association with the TOM complex is reduced upon knock-down of TOM7. The lumen of the TOM pore is crucial for PINK1 association with the outer membrane. TcPINK1 blocks the TOM pore in depolarized mitochondria.

show abstract

“…Tom70 critical mitochondrial functions are not only limited to protein import. Tom70, in concert with Tom20, has been implicated in complexes that contain Pink1 following depolarization; however, this has not been consistent across experimental reports which have varying degrees of sensitivity for detecting transient interactions [77,95]. Studies have shown that the interaction between Tom20 and Pink1 can be disrupted by celastrol, which inhibits Pink1 mitophagy providing evidence for the Pink1-Tom20 interaction and its importance in Pink1/Parkin mediated mitophagy [96].…”

Section: The Roles Tom20 and Tom70 In Mitochondrial Homeostasis Human Disease And Therapeuticsmentioning

confidence: 94%

A Biochemical and Structural Understanding of TOM Complex Interactions and Implications for Human Health and Disease

Pitt

Buchanan

2021

Cells

View full text Add to dashboard Cite

The central role mitochondria play in cellular homeostasis has made its study critical to our understanding of various aspects of human health and disease. Mitochondria rely on the translocase of the outer membrane (TOM) complex for the bulk of mitochondrial protein import. In addition to its role as the major entry point for mitochondrial proteins, the TOM complex serves as an entry pathway for viral proteins. TOM complex subunits also participate in a host of interactions that have been studied extensively for their function in neurodegenerative diseases, cardiovascular diseases, innate immunity, cancer, metabolism, mitophagy and autophagy. Recent advances in our structural understanding of the TOM complex and the protein import machinery of the outer mitochondrial membrane have made structure-based therapeutics targeting outer mitochondrial membrane proteins during mitochondrial dysfunction an exciting prospect. Here, we describe advances in understanding the TOM complex, the interactome of the TOM complex subunits, the implications for the development of therapeutics, and our understanding of the structure/function relationship between components of the TOM complex and mitochondrial homeostasis.

show abstract

The plant triterpenoid celastrol blocks PINK1-dependent mitophagy by disrupting PINK1's association with the mitochondrial protein TOM20

Cited by 23 publications

References 55 publications

Celastrol exerts anti‐inflammatory effect in liver fibrosis via activation of AMPK‐SIRT3 signalling

Celastrol exerts anti‐inflammatory effect in liver fibrosis via activation of AMPK‐SIRT3 signalling

The role of the individual TOM subunits in the association of PINK1 with depolarized mitochondria

A Biochemical and Structural Understanding of TOM Complex Interactions and Implications for Human Health and Disease

Contact Info

Product

Resources

About